News Release

Joslin Study Finds Insulin Resistance Causes Gallstones

BOSTON – July 22, 2008 – It has been known for more than 100 years that gallstones are more common in obese individuals. Now, researchers at the Joslin Diabetes Center have determined that insulin resistance is likely the reason why.

“This is a very exciting discovery not only because we now have an answer to something that has been a puzzle for more than a century, but also because of its potential therapeutic implications,” said lead author Sudha Biddinger, M.D., Ph.D., a researcher in the Joslin Section on Obesity and Hormone Action.

The research, which is published in the current issue of Nature Medicine, demonstrates a link between insulin resistance and the development of gallstones in mice that lacked insulin receptors in their livers.

“Obesity is associated with increased secretion of cholesterol into the bile. The excess cholesterol accumulates in the gallbladder, which can lead to the formation of painful gallstones,” said Biddinger. “This study shows that insulin resistance is key to this process, as the lack of insulin receptors in the liver was sufficient to promote gallstones in that group of mice.”

In the study, mice were fed a high-cholesterol diet for one week. Thirty-six percent of the insulin resistant mice developed gallstones, compared to none in the control group.

According to the paper, a regulatory protein involved in diabetes called FOXO1 is the cause.

“FOXO1 is regulated by insulin, so when there is insufficient insulin, FOXO1 is turned on,” Biddinger explained. “This causes the liver to produce glucose, which leads to diabetes. This study demonstrates that FOXO1 also increases cholesterol secretion into the bile, leading to gallstones.”

Gallstones are part of the metabolic syndrome, a collection of symptoms related to obesity – including glucose intolerance, hypertension, lowered HDL (“good”) cholesterol and elevated triglycerides – that affects up to one-quarter of all Americans.

According to Biddinger, targeting FOXO1 with new drugs could prove effective in both the prevention and treatment of diabetes as well as gallstones.

“We may be able to reverse or prevent elements of the metabolic syndrome,” she said.

The finding also provides more evidence to show that the most important features of the metabolic syndrome do have a common cause.

“This is another piece of data to show that diabetes, gallstones and cardiovascular disease are all causally linked to insulin resistance,” said Biddinger.

The study was funded in part by grants from the National Institutes of Health, the Joslin Diabetes and Endocrine Research Center and the Veterans Affairs Merit Review Program.

Others participating in the research included C. Ronald Kahn, Head of the Joslin Research Section on Obesity and Hormone Action and the Mary K. Iacocca Professor of Medicine at Harvard Medical School; Joel T. Hass, Olivier Bezy and Enxuan Jing, of the Joslin Diabetes Center; Bian B. Yu, Harvard Medical School; Terry G. Unterman, University of Illinois at Chicago College of Medicine and Jesse Brown VA Medical Center, Chicago; and Martin C. Carey, Harvard Medical School and Brigham and Women’s Hospital, Boston.